Tempering apparatus with testing device and method for testing a tempering apparatus

ABSTRACT

The invention relates to a tempering apparatus for tempering a sample comprising: at least one tempering block configured for receiving at least one sample, at least one tempering device arranged for tempering the tempering block, at least one temperature measurement device assigned to the tempering device, at least one control loop to which the tempering device and temperature measurement device are assigned to, at least one control device configured for control of the tempering of the tempering block, wherein the tempering apparatus comprises at least two temperature measurement devices assigned to the control loop, and that to the tempering apparatus a testing device for performing a test method is assigned to, wherein the testing device comprises a signal-connection to at least one of the at least two temperature measurement devices, such that at least one testing quantity of the tempering apparatus is detectable, which characterizes the operational status of the tempering apparatus.

The invention relates to a tempering apparatus for the tempering of atleast one sample with testing device and a method for testing atempering apparatus.

Tempering apparatus are being used for example as thermostats,thermomixers or thermocyclers in examination-, research- or fabricationlaboratories, for example for bringing a liquid sample to a desiredtemperature. The precise adjustment of predetermined temperatures insamples is in particular important for chemical reactions, whosesuccessful execution depends in a critical way on the compliance with atleast one certain temperature or with a temporarily changing temperatureprofile. An example for such a chemical reaction is the polymerase chainreaction (PCR). By such a PCR reaction DNA-sequences can be efficientlyamplified, for which reason said method is applied with increasingimportance, for example in pharmacy, medicine, research or forensicscience.

The precise maintaining of certain temperature values, to which a sampleis cyclically subjected during a PCR tempering program, is critical forthe successful execution of a PCR, in particular of a quantitative PCR.In a PCR, the cycle periods of denaturation, primer hybridization andelongation are controlled by different precisely defined temperaturelevels. The quality of the PCR critically depends on the capability ofthe components of the tempering apparatus being used and thus on itsoperating condition. In particular if, for example, for medical or legalmedical reasons high demands are made on the reliability andreproducibility of a PCR, the control of the operating condition of thetempering apparatus being used becomes important.

It is convenient for tempering apparatus with electrically adjustabletempering devices as, for example, Peltier elements, to set a desiredtemperature by means of a control loop, whose actuating member is thePeltier element and whose measuring member comprises a temperaturesensor. In said control loop the actuating member is operated with theobjective of bringing the temperature measured by the measuring memberin accordance with a set temperature. However, failures of such anapparatus can occur, which compromise its capability, but which dothereby not impede the function of the apparatus during the proceedingoperation in a way such that it is directly recognizable by the user.Such failures can be, for example, performance variations of thetempering device over its age or the drift of sensors. In particular forthe examination of the operability of the temperature sensors it isknown to make use of external thermometer and calibration sets whichmeasure a temperature at the apparatus. However, such an examinationrequires a relatively high effort in hardware, manpower and expenditureof time.

It is object of the present invention to provide an improved temperingapparatus, which, in particular, operates reliably and at which, inparticular, possible operation failures are easily detectable, and whoprovide an improved method for testing the function of a temperingapparatus.

Said object is made by the tempering apparatus according to claim 1 andthe method according to claim 6 of the present invention. Preferredembodiments of the invention are subject of the sub-claims.

The tempering apparatus according to the invention for the execution ofa tempering program with at least one sample, in particular a PCRsample, comprises at least one tempering block, which is configured forthe reception of at least one sample, at least one tempering device,which is arranged for the tempering of said at least one temperingblock, at least one temperature measurement device, which is assigned tosaid tempering device, at least one control loop for controlling atemperature, to which at least one tempering device and at least onetemperature measurement device, which is assigned to said at least onetempering device, are assigned, at least one control device, which isconfigured for the control of the tempering of the at least onetempering block, wherein the tempering apparatus comprises at least twotemperature measurement devices, which are assigned to at least onecontrol loop, and wherein at least one test device for the execution ofa test method is assigned to the tempering apparatus, wherein said testdevice comprises a signal-connection with at least one of said at leasttwo temperature measurement devices, such that by means of saidsignal-connection at least one test quantity of the tempering apparatusis determinable, which characterizes the operating condition of thetempering apparatus.

Such a tempering apparatus preferably is a thermomixer for thesimultaneous mixing and tempering of at least one sample, or is athermostat, which is configured for the execution of a tempering programof at least one sample. The tempering program thereby comprises at leastthe step of tempering at least one sample to a least one targettemperature. This is preferably carried out by the manual or automaticsetting of at least one set temperature as a target temperature at saidat least one control loop.

Further, said tempering apparatus preferably comprises the function of athermocycler or is configured as a thermocycler. The latter ispreferably appropriate for the execution of a PCR reaction within atleast one PCR sample. Said tempering apparatus is preferably athermocycler. The tempering program thereby preferably comprises atleast the tempering steps of a PCR cycle during whom the PCR sample istempered in a temporal sequence to at least two or three temperatures.By means of a single tempering program a PCR reaction within at leastone PCR sample is preferably executed by repeating the tempering stepsof a PCR cycle multiple times, in particular 10 to 70 times. It can bedesirable to find out the critical temperature levels of a PCR byapplying a spatial temperature gradient, i.e. a spatially changingtemperature profile with at least two different temperatures. For saidpurpose, a temperature gradient is generated in the tempering blockalong a distance, along which also a plurality of PCR samples arearranged to, which therefore are exposed to different temperatures,which lead to PCR results of differing quality. The temperature gradientcan, for example, be generated by at least two tempering devices, whichare arranged below the tempering block, as it is described in the WO98/020975 A1. This offers the advantage that the tempering block canalso be brought to a uniform temperature by generating the sametemperature by means of said at least two tempering devices. Moreover, atemperature gradient can be used to hold the samples, which are providedin the receptacles of a tempering block at different temperatures whichis, for example, reasonable if the samples are group-wise runningthrough different reaction phases. Thus, a temperature gradient can havecontinuous temperature changes or can be step-shaped. Alternatively, thegeneration of a temperature gradient can be provided by otherarrangements, wherein at least two different temperatures are applied tothe tempering block. The tempering apparatus can comprise one or moretempering devices, possibly even in each case one for a low number ofsamples, for example one for each sample or one for two samples.

Other possible tempering apparatus are work stations and otherapparatus, which can apply a tempering program simultaneously to one ormore samples.

The tempering block is preferably configured according to the temperingblock described in WO 98/020975 A1. A tempering block here refers to acomponent whose configuration allows to temper at least one sample,which is arranged at or in the tempering block. Preferably, thetempering block comprises at least one integrally formed, preferablysubstantially cuboidal-shaped component, made from a wellheat-conducting material, in particular metal, for example aluminium orsilver. It is moreover possible and preferred that said tempering blockis divided into at least two, in particular three, four, five, six ormore integrally formed sections made from a well heat-conductingmaterial, which are separated by a worse heat-conducting medium ormaterial. Within said component or within each of said sections,preferably at their upper surface, at least one receptacle for a sampleor a sample vessel is arranged. Said receptacle is preferably arrangedas a recess at the surface of said section or said tempering block. Saidreceptacle or the recess are preferably configured for a large-areacontacting of a sample vessel, for achieving an efficient heat transferfrom the tempering block to the sample vessel and to the samplecontained therein. Whenever a tempering block is mentioned in thefollowing, it also refers to a tempering block section, if not describedotherwise or if not reasonable.

Preferably, said tempering block is configured for the reception of aplurality of samples or sample vessels. Preferably, said tempering blockis configured for the reception of at least one sample plate, at which aplurality of sample vessels are arranged side by side. Such a sampleplate is preferably a microtiter plate or a PCR plate. Herein, thenumber of sample vessels is, in particular, respectively preferred 2, 4,8, 12, 16, 24, 48, 96, 384 or 1536.

The tempering device is preferably assigned to a control loop and ispreferably an electrically controllable device. The “assignment” of acomponent part, for example that of a tempering device or a temperingapparatus to a control loop, involves in the scope of the presentinvention preferably the functional assignment, according to which thecomponent part takes over a function of the control loop and for examplecontributes as a part of the control loop to the regulation of thetemperature of at least one section of the tempering block, and involvesthat, for example, a tempering device serves as an actuating member ofthe control loop. Preferably, said tempering device comprises a Peltierelement. However, another type of tempering device can be provided, forexample comprising an electrically resistive element. For the temperingof said at least one tempering block the tempering device is preferablyarranged under its underside. The tempering device preferably contactsthe tempering block in a large-area manner, wherein said temperingdevice provides a dimensioning, which allows the tempering of aplurality of samples by means of a single tempering device. To achievethis, the tempering device is preferably arranged below a plurality ofreceptacles for samples or sample vessels, which are arranged above saidtempering device in the tempering block.

To each tempering device at least one temperature measurement device isassigned. Therefore, said temperature measurement device is appropriateto measure the temperature, which is adjusted to said tempering block bymeans of said tempering device. However, the measured temperature can ina lower extent also be influenced by such tempering devices to which thetemperature measurement device is not assigned to. The assignment of atemperature measurement device to a tempering device, which is assignedfunctionally to a control loop, preferably involves that also saidtemperature measurement device takes over a function of the control loopand, for example, contributes as a part of the control loop to theregulation of the temperature of at least one section of the temperingblock and that, in particular, said temperature measurement deviceserves as a measuring member of the control loop.

For the detection of the temperature of the tempering block saidtemperature measurement device is preferably arranged at said temperingblock. The temperature measurement device is preferably arranged in adistance from said tempering device. Said distance is preferably suchthat it corresponds to a distance between the tempering device and areceptacle of the tempering block. This offers the advantage that bymeans of said temperature measurement device the temperature can bemeasured, which is pending at said receptacle and which is thus appliedto said sample vessel. However, the distance can also be chosendifferently. Further, it is preferred that at least one temperaturemeasurement device is arranged in a boundary area of a tempering block.Preferably, at least two tempering devices are arranged at the temperingblock in a maximum possible distance, wherein the maximum distance can,for example, be determined by the length or the width of the temperingblock (-section) and/or the dimensions and/or other predeterminedparameters, for example the position of arrangement of the temperaturemeasurement device at the upper side or the border side of the temperingblock. The border side of the tempering block can provide a differenttemperature than a central area of the tempering block due to theenvironmental temperature or due to the convective heat transport ofenvironmental air. Therefore, the measurement at the border side of thetempering block is in particular of advantage to achieve temperaturecontrol there. Further, the measurement in the border area can be ofadvantage to generate and control a temperature gradient within thetempering block, which extends from one end, i.e. border area of thetempering block to the other end. The measuring at the border area canmoreover also be of advantage, because the heat flow within thetempering block will not be hindered by the temperature measurementdevice. A temperature measurement device is preferably attached to thetempering block, for example adhered to, or preferably at least in partincorporated into a recess or opening of the tempering block. Thetemperature measurement device is preferably an electronic component andcan, for example, comprise a semiconductor temperature sensor, athermoelement or a pyrometer.

Preferably, at least one temperature measurement device is arranged in alow distance or in direct contact with at least one tempering device.Said low distance is preferably lower than 0.5 times, 0.25 times or 0.1times a thickness of the tempering block. Said temperature measurementdevice is preferably functionally assigned to a control loop orpreferably not functionally assigned to a control loop. The advantage ofa low distance is that a shorter distance for heat transfer between thetemperature measurement device and the tempering device is generated,whereby a change of the temperature of a tempering device can bedetected faster than in the case of a larger distance between thetemperature measurement device and the tempering device. This is, inparticular, of advantage to test the operability of the temperingdevice, in particular by means of the test method according to theinvention. A shorter overall duration of the test method can effect thatit can be tested more frequently, whereby the reliability of thetempering apparatus can be monitored in a better way.

The tempering apparatus further preferably provides at least onetemperature measurement device, which is configured as safety sensor.Such a safety sensor is preferably signal-connected to the controldevice and configured to detect a predetermined extreme temperature inthe tempering apparatus, whose detection preferably leads to a safetyprocedure of the tempering apparatus, for example to the output of awarning signal or to the shut-down of the tempering apparatus. A safetysensor is preferably arranged for the safeguarding of temperature of thetempering block in the vicinity of a temperature measurement device,which is assigned to a control loop. The safety sensor is not assignedto a control loop. In this way, a malfunctioning control loop lessprobably also involves also the malfunction of the safety sensor. Said“vicinity” of a temperature measurement device is preferably an area,which lies in a distance to said temperature measurement device, whereinthe distance is preferably lower than the maximum distance of twotemperature measurement devices of the tempering apparatus, which areassigned to at least one control loop, is preferably lower than theminimum distance of two temperature measurement devices of the temperingapparatus, which are assigned to a control loop, is preferably lowerthan a width of the tempering device, is preferably lower than theheight of a tempering block, which can, for example, 3 cm, and ispreferably lower than 1 cm. A safety sensor can, in particular, bearranged in direct or indirect contact with another temperaturemeasurement device, in particular without being separated from a sectionof the tempering block or from the environmental air.

A control loop is preferably assigned to a control device, which isconfigured for the control of the tempering of the at least onetempering block. However, it is also possible and preferred, that atempering device and at least one temperature measurement device, whichis assigned to said one tempering device, are provided, which are onlyat least temporarily assigned to no control loop by having them excludedor being switched off from their control functions (actuating member,measuring member) by way of program control. Such a control of saidtempering device and said temperature measurement device offers afurther increased flexibility for the configuration of a test method.Further, the independency of a component, in particular of a temperaturemeasurement device, on the control loop can lead to an increase of thereliability of testing said control loop by means of said component.During the regulation of the temperature in a tempering block by meansof said control loop, said control device is signal-connected to said atleast one control loop and to at least one temperature measurementdevice, which is assigned to said at least one control loop.

Within the scope of the invention two devices are considered to besignal-connected, between which signals can be exchanged. Said signalsare thereby preferably bound to a medium, as for example to anelectrical conductor or semiconductor. It is possible and preferred,that said signals, which are exchanged between said two signal-connecteddevices, are exchanged via a mediation device, by, for example, lettinga first device sending a signal to the mediation device, where thesignal is buffered and is optionally also modified, before a seconddevice accesses the buffered signal, to receive it. For example, saidtemperature measurement device of a control loop can supply a measuringsignal, which is buffered by a memory device of the control loop suchthat the testing device can access said memory device for receiving saidmeasuring signal. In this example the testing device is signal-connectedto the temperature measurement device. However, it is also possible thatsaid signals are transferred without being bound to a conductingmaterial, i.e. being transferred to the space, as for example possiblefor electromagnetic rays (for example radio waves or infrared light) aswell as by sound waves through a space, which is at least filled by gas.Herein, by the term “signal-connected” uni- as well as bidirectionaltransmission lines are covered.

To each control loop preferably at least two temperature measurementdevices and at least one tempering device, which is assigned to saidtemperature measurement devices, are assigned. Conventional temperingapparatus, in particular thermocycler, commonly possess more than onetempering device per control loop and temperature sensor. This way, themalfunction of a tempering device can generally not be recognized,because the deviations in the performance do not mandatory lead to afailing temperature at the temperature measurement device, which isprovided for measuring the temperature of the section in the temperingblock, which is tempered by said tempering device. Nevertheless, saiddeviations in performance lead to an inhomogeneous distribution oftemperatures at said sample block, because different power rates areintroduced at different locations via the single tempering devices.Moreover, incorrect sensor values, for example caused by changes of thecontacting or by drift, are not recognized. For the improvement of saidsituation, at least one temperature measurement device and, inparticular, a second temperature measurement device are assigned to eachtempering device. This way, a number of test method can be executed in aflexible way, in particular by means of the testing device. By thecomparison of test quantities, in particular the comparison oftemperature measuring values and of temperature changing velocities,with reference values or in particular with other measured testingquantities, the operating condition of a network of components, ofsingle components of the tempering apparatus or of the overall temperingapparatus can be determined. The testing device is preferablysignal-connected to at least one, in particular to each control loop andpreferably signal-connected to at least one, in particular eachtemperature measurement device, which is assigned to said control loop.

Especially preferred, the tempering apparatus comprises at least onecontrol loop, to which at least two tempering devices and at least twotemperature measurement devices are assigned to, wherein at least onetemperature measurement device is assigned to each tempering device. Inparticular, the tempering apparatus comprises preferably a number ofcontrol loops, to which respectively two tempering devices and twotemperature measurement devices are assigned to. Said number ispreferably 2, 3, 4, 5, 6, 7, 8 or higher.

Preferably, exactly one temperature measurement device is assigned toeach tempering device and preferably exactly said tempering device isassigned to said temperature measurement device. It is furtherpreferred, that at least two temperature measurement devices, inparticular exactly two, are assigned to one tempering device. This way,the testing of the tempering apparatus can be further improved and berendered in particular more reliable and more precise, and this way thetempering apparatus can be improved. Further, preferably exactly twotemperature measurement devices are assigned to each tempering deviceand exactly said tempering devices are assigned to said two temperaturemeasurement devices.

The tempering apparatus preferably comprises at least two temperingdevices, which are arranged for the tempering of said at least onetempering block, at least two temperature measurement devices wherein atleast one temperature measurement device is assigned to each temperingdevice, and at least one first control loop and one second control loop.The use of at least two control loops may, in particular, allow to applyat least two different temperatures to said at least one temperingblock. Preferably, said at least two tempering devices are arranged forthe generation of a temperature gradient, that is a temperature profilewith at least two different temperature values, which extends withinsaid at least one tempering block. It shall be understood, that by meansof two different tempering devices also a single temperature can beapplied to at least one tempering block. Preferably, said testing devicecomprises a signal-connection to each tempering device and to eachtemperature measurement device of said first and second control loop,wherein by means of the testing device a first testing quantity isdeterminable, which is assigned to said first control loop, and whereina second testing quantity is determinable, which is assigned to saidsecond control loop. Preferably, said testing device comprises a meansfor the comparison of said two testing quantities or for the comparisonof said testing quantity with another reference quantity. The referencequantity can be a stored quantity or a measured quantity, in particulara testing quantity.

Said control device preferably comprises electrical circuits, which areconfigured for the control of a tempering of the at least one temperingblock. Further, said control device preferably comprises means for thedigital data processing. The control loop preferably comprises aprocessing unit, which can be a CPU, a microprocessor or amicrocontroller.

Preferably, said control device comprises circuits, which are configuredfor processing a program code, in particular for the processing ofprograms for the temperature regulation or programs for executing a testmethod, in particular the test method according to the invention.Further, the control device preferably comprises at least one memoryunit for the storage of data or signals, which preferably is alsoremovable from the control device. Said memory unit preferably comprisesdata storage for the temporary storage of data, for example RAM and/ordata storage for the permanent storage of date, for example hard disc orflash memory. Further, said control device preferably comprises at leastone interface for establishing a signal-connection between said controldevice and another device, for example a testing device in an externalembodiment, to an external data storage, to a control apparatus, to anexternal PC, to a control panel or to another device. Further, saidcontrol device preferably comprises circuits, for example powerelectronics, for a control of components for the energy supply, whichcan serve, for example, for the power supply of said control device,said at least one tempering device are said at least one temperaturemeasurement device. For the regulation of a temperature within saidtempering block by means of said control loop, said control device issignal-connected to said at least one control loop and to at least onetemperature measurement device, which is assigned to said at least onecontrol loop.

The testing device is preferably arranged in the tempering apparatus andis preferably constructionally integrated in the control device.However, it is also possible and preferred, that the testing device isan at least substantially separate component. The testing devicepreferably comprises electrical circuits, which are appropriate forprocessing signals, which are required for the execution of the testingmethod. Preferably, the electrical circuits of the testing device are atleast substantially separated from the circuits of the control device,forasmuch as no signal lines have to be used together. In that case, thecircuits of the testing device are preferably arranged in a spatialoffset to the circuits of the control device. This offers the advantagethat their arrangement is more flexible and can, for example, beconfigured for minimizing detrimental thermal or corrosive effects, forexample by encapsulation. In this way, the reliability of the testingdevice and thus of the tempering apparatus can be improved. The testingdevice preferably comprises at least one signal-connection to at leastone tempering device, in a way that it puts out signals, which influencethe operating condition of the tempering device. The testing devicefurther preferably comprises at least one signal-connection to at leastone control loop, by being capable of exchanging signals with at leastone component of the control loop, for example of its actuating member,which controls the supplying power to the tempering device, or itsmeasuring member (sensor). Further, the testing device is preferablysignal-connected to at least one power control device, which controlsand measures the power, which is put in to a tempering element.

It is further possible and preferred, that the testing device, which isassigned to said tempering apparatus for the execution of a testingmethod, is arranged externally outside the tempering apparatus, whereinsaid testing device comprises a signal-connection to said at least onetemperature measurement device. Said signal-connection at such a testingdevice in external embodiment preferably takes place via an interface,which is provided at said tempering apparatus, in particular at saidcontrol device. This way it is possible that a central control of thetesting method takes place, for example by means of a control center oran laboratory information management system (LIMS), which, inparticular, can control a plurality of tempering apparatus.

The execution of a testing method by means of an external testing devicepreferably takes place without a manual intervention of a user to saidtempering apparatus and preferably takes place automatically. Anexternal testing device can, in particular, comprise a control device,which can comprise a microcontroller, an input device, for example akeyboard, an input panel and, an output device, for example a display.Preferably, an external testing device is a PCR workstation. Inparticular, an external testing device can be the component of anexternal control center or control device, for example a PC orworkstation, which administrate further tasks for the control of furtherdevices, for example in an automatic measuring system or by means of aLIMS.

Preferably, said tempering apparatus and, in particular, said controldevice are configured for the remote control of at least one function ofthe tempering apparatus or of a component of said tempering apparatus.Preferably, said tempering apparatus, in particular said control device,is configured for the remote access to at least one component of saidtempering apparatus. Preferably, said tempering apparatus, in particularsaid control device, is configured for the remote access of an externaltesting device, which is assigned to said tempering apparatus for theexecution of a testing method. By having also said external testingdevice comprising a signal-connection to a control loop and to atemperature measurement device, the execution of the testing method cantake place remote controlled. It can, for example, be provided that thetesting method is executed remote by a service professional or isexecuted automatically, to determine the operating status of saidtempering apparatus and are to gain operational data, in particular saidat least one testing quantity of the tempering apparatus, for themonitoring of functions or the remote diagnosis of the operatingcondition of said tempering apparatus. In particular, it can be providedthat said external testing device is part of a diagnosis and maintenanceapparatus, which a service professional connects to said temperingapparatus for the execution of a testing device. However, it is alsopossible and preferred that said external testing device stands insignal-connection to said tempering apparatus over larger distances.Preferably, said tempering apparatus, in particular said control device,is configured for the signal-connection via a network- orinternet-connection or similar long distance lines. In this case, anexternal testing device can stand in signal-connection to said temperingapparatus via said long distance line and start a testing method andexecute it. Since a signal-connection can also take place wireless andthus also over larger distances and through walls and obstacles, forexample by an electromagnetic signal transfer in the GHz range, atesting of a testing quantity of said tempering apparatus can beconfigured even more flexible.

The tempering apparatus further preferably comprises a starting device,which is appropriate for the manual and/or automatically starting of atesting method, which is executed by said testing device. The startingdevice is preferably structurally integrated into the testing device orthe control device, but can also be realized separately. The startingdevice preferably comprises circuits, which are appropriate forprocessing starting signals and/or in particular for the processing of astarting program code. The starting device is preferably configured fora manual starting, in particular, for a direct or a time-delayedstarting of a testing method of the testing device of said temperingapparatus. The starting device can comprise at least one input device,for example an actuation element as perhaps are a knob or a sensor fieldon a control panel of the tempering apparatus, which is signal-connectedto said testing device and configured at least for effecting a startingsignal by the user. Further, the starting device is preferablyconfigured for the automatic starting of a testing method of the testingdevice of said tempering apparatus. The automatic starting also includesa semi-automatic starting. For performing a semi-automatic starting, thestarting device is preferably configured for letting the actuation of aninput device by the user lead to the automatic, in particular programcontrolled starting of the testing method, for example by means of astarting program. In particular, the starting device is equipped with atleast one starting program, which the user can choose by means of saidinput device, to determine the starting of at least one testing device.

The starting device, in particular a starting program, is preferablyconfigured in a way that the starting of a testing method takes placebefore or after each measurement on said at least one sample, which isperformed by means of said tempering apparatus, and takes place, inparticular, for each execution of a tempering program. The startingdevice, in particular a starting program, is further preferablyconfigured the way that starting the testing method takes place inregular periods automatically after each n^(th) (n≧1) start-up of thetempering apparatus or after each n^(th) application of the temperingapparatus in a tempering program. Further, the starting device, inparticular a starting program, is preferably configured in a way thatstarting the testing method is provided automatically after a determinedoverall operating time of the tempering apparatus. Further, the startingdevice, in particular a starting program, is preferably configured in away that starting the testing method takes place automatically after apredetermined idle time of the tempering apparatus, by letting thetempering apparatus switch on, in particular self-acting, from astand-by mode onto execute said testing method. The starting device, inparticular a starting program, is further preferably arranged in a waythat starting the testing method and the type of the testing method tobe performed is assigned to a certain type of tempering program. Saidassignment can be permanently stored in the tempering apparatus or thetesting device or can be assigned by the user, in particular by means ofthe input device. It can, in particular, be provided that the userautomatically is informed on the testing results at the execution of thetempering programs or that a certificate is issued which providesinformation on the operating condition of the tempering apparatus, inparticular before, during or after the execution of the temperingprogram. By means of said versatile starting methods, the reliability ofthe tempering apparatus can be improved and at the same time a testingmethod can be performed more flexible and comfortable for the user.Preferably, the tempering apparatus, in particular the starting device,is configured for the performance of multiple, in particular of all ofsaid described starting alternatives.

The testing device is configured for the execution of a testing method.A testing method includes a series of processes within said testingdevice, which is signal-connected to said tempering apparatus, whereinby means of said processes at least one testing quantity of thetempering apparatus is determinable, which characterizes the operatingcondition of the tempering apparatus. Said process include, inparticular, the generation of said starting signal, as well as thecontrol of at least one temperature measurement device and theprocessing of the measured data. The execution of a testing methodpreferably takes place by means of processing at least one test programcode. Further, the execution preferably takes place before or after theexecution of a tempering program of said tempering apparatus. However,it is also possible and preferred that the testing method takes place inpart or completely during the execution of the tempering program of thetempering apparatus. Preferably, the testing device is configured forthe execution of a testing method at least in part during the executionof a tempering program. By this way, on the one hand time can be savedand, on the other hand, a test can be obtained, which individuallyguards the progress of a tempering program, for example by determiningfor each adjusted temperature value or for each approaching of atemperature value a testing quantity, which characterizes the operatingcondition of the tempering apparatus during said step. This allows, forexample, to issue for each tempering program a detailed certificate,which improves the reliability of, for example, the performance of aPCR.

Further, the tempering apparatus preferably comprises at least one powercontrol device, which is configured for the control and/or measurementof the power, which is put out to at least one tempering device, inparticular the electrical power. Further, the testing device preferablycomprises a signal-connection to said at least one power measurementdevice, such that the power, which is put out to such a temperingdevice, can be determined and can be available as data for the use in atesting method, in particular within a testing method according to theinvention. Such a power measurement device for measuring an electricalpower P=U·I can, for example, comprise a digital power-meter. In adigital power-meter, instantaneous values for current and voltage aredigitized by means of a preferably high sampling rate and are computedin a calculation unit to determine the electrical power P=U·I.

The tempering apparatus, in particular the control device, preferablycomprises a timer, which preferably stands in signal-connection to thetesting device. Preferably, the testing device comprises at least onetimer.

The tempering apparatus and/or the testing device are, respectively,preferably configured for the execution of the testing method accordingto the invention.

Further features and advantages of the tempering apparatus according tothe invention can be derived from the following description of thetesting method according to the invention and its preferred embodiments.

The object underlying the invention is further solved by the methodaccording to the invention for testing at least a first testing quantityof a tempering apparatus. The method can, in particular, be performed bytempering apparatus, which are configured as thermomixers, thermostatsor thermocyclers.

The method according to the invention for testing at least one firsttesting quantity of a tempering apparatus, which serves for thetempering of at least one sample, in particular a PCR-sample, whereinsaid tempering apparatus comprises at least one tempering block, whichis configured for the reception of at least one sample, at least onefirst tempering device, which is arranged for the tempering of said atleast one tempering block, at least one first temperature measurementdevice and at least one second temperature measurement device, which areassigned to at least one control loop, wherein at least one temperaturemeasurement device is assigned to each tempering device, at least onecontrol device, which is configured for the control of the tempering ofthe at least one tempering block, an at least one first control loop, towhich said at least one first tempering device and said at least onefirst temperature measurement device, which is assigned to said at leastone first tempering device, are assigned to, comprises the followingsteps: Starting of the method; operating at least said first temperingdevice for the duration of at least a first period from at least a firsttime; detecting at least one measurement temperature by means of said atleast one temperature measurement device, which is assigned to saidfirst tempering device, at least at a second time; detecting at leastone first testing quantity of the tempering apparatus and using said atleast one measured temperature; comparison of said first testingquantity with a reference quantity.

It is an advantage of said testing method according to the inventionthat the operating condition of a tempering apparatus and itscomponents, in particular the operating condition of a network ofcomponents, can be monitored, wherein said network comprises at leastone first tempering device and further said at least one temperaturemeasurement device, which is assigned to said at least one firsttempering device. The detected first testing quantity can be assigned atleast to said first tempering device and to at least said firsttemperature measurement device. In particular, said first testingquantity is assigned to said component network and characterizes itsoperating condition. By the comparison of said first testing quantitywith a reference quantity, which, for example, can be stored in a memorydevice of the tempering apparatus, which is made available via aninterface or which is calculated by the controlled device, the operatingcondition can be monitored. In particular in the case if more than onetempering devices are provided or if measurement data from at least twodifferent temperature measurement devices are available, the operatingcondition of said tempering apparatus can be monitored by the comparisonof two or more testing quantities, wherein, for example, a first testingquantity can be assigned to a first tempering device and a secondtesting quantity can be assigned to a second tempering device or a firsttesting quantity can be assigned to a first temperature measurementdevice or a second testing quantity can be assigned to a secondtemperature measurement device.

Preferably, in addition to the first testing quantity, that is either atleast in part simultaneously or at least in part temporarilysequentially, a second testing quantity is detected. The latter can beassigned to a second temperature measurement device and/or to a secondcontrol loop which can be configured analogical to said first controlloop. This offers the advantage that the operating condition of thetempering apparatus can be characterized also without using a referencequantity being present as stored data by comparing said first and saidsecond testing quantity and by indicating a failure in the case of adeviation within a predetermined tolerance. Thereby, the reliability ofthe testing method and its functionality can be further enhanced.

In a first embodiment of the method according to the invention itadditionally refers to the testing of a second testing quantity of thetesting apparatus, wherein to said first control loop at least onesecond tempering device and at least said one temperature measurementdevice, which is assigned to said second tempering device, are assignedto, and wherein the method comprises the following steps: Operating saidsecond tempering device for a duration of at least a first period fromat least a first time; detecting at least one measurement temperaturefrom said at least one second temperature measurement device, which isassigned to said second tempering device, at least at a second time;determining at least a second testing quantity of the temperingapparatus by using said at least one measurement temperature; comparisonof said second testing quantity with a reference quantity. The method istherefore useful for such tempering apparatus, which, for example forthe increasing of the tempering performance, provide at least twotempering devices, to which respectively at least one temperaturemeasurement device is assigned to. By letting the method individuallydetect the measurement temperatures of said temperature measurementdevices, two testing quantities can be determined, which individually orin comparison with each other give information on the operatingcondition.

Preferably, for said one first control loop two testing quantities aredetermined, such that their comparison gives information on theoperating condition of the tempering devices and temperature measurementdevices, which are used in said control loop. Further, by saidconfiguration of the testing method and the tempering apparatus it canbe recognized with a high probability whether a functional failure ispresent at a network of a tempering device and its assigned temperaturemeasurement device. However, without further provisions it cannot berecognized whether in the case of a failure which is recognized for sucha network, the cause lies in a malfunctioning tempering device or in amalfunctioning temperature measurement device. However, said problem canbe solved by means of further constructive provisions that is with thetempering apparatus in a further configuration and the testing method inits second embodiment. In this case, the tempering devices and thetemperature measurement devices of a control loop have to be configuredto be selectively excludable from the system, and have, for example, tobe configured disengageable by means of the testing device. In such acase it is, in particular, possible in a tempering apparatus, at whicheach control loop comprises at least two tempering devices and at least,respectively, one temperature measurement device, which is assigned tosaid tempering device, by means of such a configuration of the methodaccording to the invention, to determine the individual component of thetemperature measurement devices and tempering devices which ismalfunctioning.

For that purpose, a control loop preferably provides the same number oftempering devices and temperature measurement devices, in particular atleast two tempering devices and at least two temperature measurementdevices, in particular a number of three or four and in particularpreferred two. At the normal tempering operation of the temperingapparatus, the two tempering devices T1 and T2, which are assigned to atleast one section of the at least one tempering block in the temperingapparatus, and the two temperature measurement devices S1 and S2, whichare assigned to the respective tempering device for the regulation oftemperature of a section, are used for the regulation of the temperatureof said section. Thereby, T1 and S1 or T2 and S2 can, respectively, bearranged for their mutual assignment respectively closer to each otherthan respectively T1 and S2 or T2 and S1. For the regulation of thetemperature, that is the tempering of said section, the temperingdevices T1 and T2 as well as the temperature measurement devices S1 andS2 are used.

First, a temperature difference is determined, which is measured byoperating the tempering device T1 within a constant period by means ofthe temperature measurement device S1 as first testing quantity.Further, a temperature difference is determined, which is determinedwithin said period by operating the tempering device T2 by means of saidtemperature measurement device S2 as the second testing quantity. Bycomparison of respectively the first testing quantity and the secondtesting quantity with a reference quantity it can first be determinedfor which network of components T1, S1 or T2, S2 a malfunction ispresent. After it, a third testing quantity and subsequently preferablya fourth testing quantity are determined. The third testing quantity isthe temperature difference, which is determined at S1 due to atemperature change by means of T2 within a predetermined period and thefourth testing quantity with the temperature difference, which iseffected at the temperature measurement device S2 within said period dueto tempering by means of T1. Hence, a temperature regulation of thetempering block (section) is initially exclusively performed via thenetwork T2, S1 and optionally afterwards exclusively via T1, S2. Thecomparison of said third testing quantity with a further referencequantity gives information on whether a malfunctioning has occurred atthe pair of component T1, S2 or T2, S1. By comparison with the first andthe second testing quantity it can be reasoned, which component T1, T2,S1 or S2 provides a malfunction. If, for example the network S1, T2provides a malfunction, which is determined by means of the firsttesting quantity, and the network S2, T2 does not provide a malfunction,which is determined by means of the second testing quantity, then amalfunction of the temperature measurement device S1 is present, if thenetwork S1, T2 shows a malfunction, which is determined by means of saidthird testing quantity. Said diagnosis can be confirmed, if the firsttesting quantity, which can be determined optionally and whichcorresponds to the network T1, S2, does not show a malfunction,

In a third embodiment of the method according to the invention itrelates also additionally to the testing of a second testing quantity ofsaid tempering apparatus, wherein said tempering apparatus comprises atleast one second control loop, which is different from said firstcontrol loop, wherein to said second control loop at least one secondtempering device and at least said second temperature measurementdevice, which is assigned to said at least one second tempering device,are assigned to, and wherein the method comprises the following steps:Operating said second tempering device for the duration of at least afirst period from at least a first time; detecting at least onemeasurement temperature from said at least one second temperaturemeasurement device, which is assigned to said second tempering device,at least at a second time; detecting at least a second testing quantityof the tempering apparatus by using said at least one measurementtemperature; comparison of said second testing quantity with a referencequantity. The method is therefore of advantage for the temperingapparatus, which comprise two or more, preferably independent, controlloops. Such tempering apparatus are used for generating a temperaturegradient in the tempering block. By letting the method individuallydetect the measurement temperatures of the temperature measurementdevices of said control loops, two testing quantities can be determined,which individually by comparison with each other or with a referencequantity give information on the operating condition.

In particular, if multiple temperature measurement devices are assignedto the tempering device for tempering apparatus, preferably a fourthconfiguration of the method according to the invention is used. Saidmethod is used for detecting a difference of measured temperatures astesting quantity of a tempering apparatus, and comprises additionally tothe steps of the method according to the invention the following steps:Detecting at least one measurement temperature from said at least onesecond temperature measurement device at least at a second time; usingsaid measurement temperature for the detection of said testing quantityby forming at least one difference of measurement temperatures of saidfirst and second temperature measurement devices, and use of saiddifference as said testing quantity. The second time, at which themeasurement temperature is detected by means of the first temperatureelement device, that is the second time of the first temperaturemeasurement device, and the second time of the second temperaturemeasurement device are preferably the same time. However, themeasurements can also take place at different time points. Saiddifference is a measure for the deviation of the operating condition ofthe tested temperature measurement devices. This configuration of themethod is in particular usable also in combination with theconfigurations of the method described above, which refer to thedetection of said second testing quantity, that means that not only saidfirst but also said second testing quantity can be a temperaturedifference, which was detected by means of two, in particular differentor even the same, temperature measurement devices.

Preferably, an absolute value, for example a time, a temperature or atime difference or temperature difference is used as testing quantity.For that purpose a set temperature is adjusted, preferably by means ofthe control loop, and the temperature value, which is measured this way,is used for the testing method. In a fifth embodiment in the methodaccording to the invention therefore comprises additionally thefollowing steps: Applying a set temperature from at least said firsttime at the control loop, to which said at least one tempering deviceand said at least one temperature measurement device, which is assignedto said at least one tempering device, are assigned to; using themeasurement temperature, which is measured at said second time, as saidtesting quantity. Preferably, thereby also the at least one measurementtemperature is detected, which is measured by said at least one firsttemperature measurement device, which is assigned to said firsttempering device, at said first time. It is further possible that—inparticular parallel to said beforementioned step—the power input of saidfirst tempering device is measured between said first and said secondtime by means of a power control device as testing quantity and iscompared with reference data for the power input of said first temperingdevice. Preferably said second time is chosen such that the temperingblock or tempering block section, which is tempered hereby, has adaptedthe set temperature within the limits of a tolerance. Preferably, themethod comprises the step that said first period is chosen such that itcomprises a delay time, for example 0 to 900 seconds, 10 to 50 secondsor preferably 20 to 40 seconds, which follow up to the time point, atwhich the tempering block or tempering block section, which is to betempered, has reached the set temperature within a tolerance, to achievea stable temperature measurement. For that purpose, preferably at timesafter said first time the measurement temperature is repeatedly detectedby means of said first temperature measurement device, for exampleperiodically. Said set temperature plus a tolerance is preferably usedas said reference quantity. However, it is also possible that saidreference quantity is different, in particular smaller, than said settemperature, such that a comparison of the measurement temperature withthe reference quantity can take place in particular before reaching theset temperature at the tempering block, such that a shortened testmethod is possible, which can lead in particular to a shortened overallduration of the testing method.

Alternatively to an absolute value, for example a time, temperature ordifference, also a temporal change of the values, for example atemperature change velocity or a rate, can be used as testing quantity.In this way, the performance parameters, which are relevant for theoperation of a tempering apparatus, can be determined and the capabilityof the apparatus can be determined. Said temporal change of values canbe described by the quotient of the value difference divided by the timedifference. Said quotient can be, for example, the temperaturedifference divided by the time. For the determination of said quotient,a period can be predefined and the temperature difference can bemeasured, which is reached at the expiry of the predefined period. Thevariable quantity in this case is the temperature difference.Alternatively, the temperature can repeatedly be measured and the timepoint and therefore the period can be detected, at which a predefinedtemperature or temperature difference is reached. The variable quantityin this case is the time or the period. As the testing quantity in bothcases either the quotient or the variable quantity can be used. If thevariable quantity is chosen as the testing quantity, then therespectively predefined (constant) value, for example a fixedtemperature difference, will also be used for the reference quantity,which is used for the comparison with the testing quantity. The use ofthe variable quantity as the testing quantity offers in particular theadvantage that the step of calculation of forming of a quotient and alsocomputation time is saved.

For said purpose, the method according to the invention in a sixthembodiment preferably comprises the steps: Detecting at least onemeasurement temperature from said at least one temperature measurementdevice, which is assigned to said tempering device, at a third time;forming the difference between two measurement temperatures, from whichthe first was measured at said second time and the other was measured atsaid third time; forming of a second period, which corresponds to thedifference of said third time and said second time; and using saiddifference between two measurement temperatures or said second period assaid first testing quantity. Said third time for all embodiments of themethod preferably lies after said second time.

Alternatively to the sixth embodiment in the method according to theinvention the seventh embodiment preferably comprises the steps:Detecting of at least one measurement temperature from said at least onetemperature measurement device, which is assigned to said temperingdevice, at a third time; forming the quotient of the difference of twomeasurement temperatures, from which the one was measured at said secondtime ant the other was measured at said third time, at a second period,which corresponds to the difference of said third time and said secondtime, and using said quotient of the difference and the second period assaid first testing quantity.

As described above, a period can be predefined and the temperaturedifference can be measured which arises upon expiration of thepredefined period. For that purpose the method in an eighth embodimentpreferably comprises the steps: Using a predefined second period; usingthe sum of said second time and said predefined second period as saidthird time. In this case, the second period is kept constant and thetemperature difference at said first temperature measurement device atthe begin and the end of said second period is detected. Said third timeis at the determination of a quotient preferably chosen such that thetempering block does not yet reach the set temperature. Then, thetemperature difference or the quotient during a period is detected inwhich the temperature of the tempering block changes continuously.However, the third time can also be chosen such that the tempering blockwithin a tolerance has already reached the set temperature.

As described above, it is also possible and preferably provided that atime difference or a quotient is used as said first testing quantitywherein the difference of the measurement temperatures is kept constant,as it is determined, at which third time said temperature differencewill be measured. For this purpose the method in a ninth embodimentpreferably comprises the steps: Repeated detecting of at least onechanging measurement temperature from said at least one temperaturemeasurement in the device, which is assigned to said tempering device,at times after said second time; comparison of said changing measurementtemperature with a comparison temperature; detecting a time, at whichsaid changing measurement temperature has reached said comparisontemperature within a tolerance and using said time as said third time.The comparison temperature is preferably said set temperature oranother, predefined temperature, for example a temperature which isstored in the tempering apparatus.

Depending on if a variably quantity or respectively said quotientaccording to the sixth or, respectively, the seventh embodiment of themethod is detected, as said temperature difference or said second periodis kept constant, other types of function failures of the temperingapparatus can be detected. By this way, the flexibility of the testingmethod is enhanced.

The tempering, in particular at the sixth or seventh embodiment of themethod, can either take place by establishing a set temperature at thecontrol loop or by establishing a constant power to the temperingdevice. At a constant temperature difference, the method according tothe tenth embodiment therefore preferably comprises the step: Applying aset temperature from at least said first time and for at least theduration of said first period to said first control loop, to which areassigned said at least one first tempering device and said at least onefirst temperature measurement device, which is assigned to said at leastone first tempering device. Thereby, said comparison temperaturepreferably is said set temperature. Further, in the case of a constanttemperature difference it is preferably provided that the method in aneleventh embodiment comprises the step: Operating said at least onefirst tempering device for the duration of at least said first periodfrom at least one first time with constant power.

For further enhancing of the reliability of the testing method and itsfunctionality it is preferably provided that one second testing quantityis detected, which is compared either with said first testing quantityor with a reference quantity.

For the case, that at least two different testing quantities aredetected by the testing method, it is preferred that the methodcomprises at least one of the both steps: Using said second testingquantity as reference quantity for comparison with said first testingquantity; using said first quantity as reference quantity for comparisonwith said second testing quantity.

For all embodiments or modifications of the method it is preferred thatsaid reference quantity is a comparison temperature, which for exampleis stored in a storage device of the tempering apparatus, or which issupplied to the tempering apparatus via a data interface.

The starting of the method preferably takes place manually by the user,preferably via an input panel at the tempering apparatus. Preferably,the starting of the method takes place selectively either manually bythe user or automatically. Further, the starting of the method takesplace preferably automatically for each measurement, which is carriedout by means of said tempering apparatus at said at least one sample, inparticular to one, in particular each, execution of a tempering programfor at least one sample, in particular before, after or during anexecution of a tempering program. Preferably, the starting of the methodtakes place automatically in regular periods automatically after eachn^(th) (n≧1) starting up of the tempering apparatus or at each n^(th)application of the tempering apparatus. Further, it is preferred thatthe starting of the method is provided automatically after apredetermined overall operation time of the tempering apparatus.Further, it is preferred that the starting of the method takes placeautomatically after a predetermined idle time of the temperingapparatus, as the tempering apparatus switches on itself automaticallyfrom a standby mode too perform said testing method. In this way thereliability of the tempering apparatus can be enhanced and at the sametime a testing method can be run in a comfortable way for the user.Preferably the tempering device is configured for the realization ofseveral, in particular all, of said described starting alternatives.

The method according to the invention is preferably configured for thepurpose to provide a short total time for its application, which ispreferably shorter than 40 minutes, preferably shorter than 30 minutes,preferably shorter than 25 minutes, especially preferred shorter than 20minutes, even more preferred shorter than 15 minutes, even morepreferred shorter than 10 minutes, even more preferred shorter than 9.5minutes and even more preferred shorter than 6 minutes. Most preferredthe total time of the method according to the present invention is under5 minutes. Further, the tempering apparatus according to the invention,in particular also its testing device, is preferably configured for theexecution of such a testing method with such a short total time. A shorttotal time offers the advantage that more time is available for theexecution of the primary function of a tempering apparatus, namely theexecution of at least one tempering program. In this way, the work flowat the application of a tempering apparatus, which runs the testingmethod according to the invention, is less delayed and the use of saidtempering apparatus becomes more efficient and comfortable. Further, ashort total time allows for carrying out the testing method more often,in particular automatically. Thereby, the reliability of the temperingapparatus is further improved. For the case, that the testing method iscompletely run during the application of a tempering program, theduration of the method can be described as zero.

The tempering apparatus according to the invention and/or the methodaccording to the invention further preferably provides a documentaryfunction, by means of which data can be permanent recorded, that is forexample permanently respectively to a power failure. Preferably, thetempering apparatus provides a documentary device, which can comprise astorage device or parts of a storage device, which is also used for thestorage of other date. Said documentary device is preferably arranged insaid tempering apparatus, but can also be configured as external device,for example as part of an external PC, which is connected to thetempering apparatus via a data interface. The documentary devicepreferably serves for the storage of a testing log file, which providesdata base entries, which for example comprise the date, the time of day,serial number, user and/or the testing result (for example ifpassed/failed). Correspondingly, the method preferably comprises thestep: Entering of at least one data base entry in a documentary deviceof the tempering apparatus. By the documentation of testing results themaintenance and thereby the reliability of the apparatus can beimproved.

The result of a testing device is preferably put out to the user. Thiscan take place visually, for example via an input panel of the temperingapparatus, and/or acoustically, for example via a loudspeaker of thetempering apparatus. Further it is preferred that the temperingapparatus according to the invention and/or the method according to theinvention comprises a certification function, by means of which acertificate of a performed testing method can be generated. For saidpurpose, the tempering apparatus is preferably configured for the outputof a certification data set in a certificate, by putting out allrepresenting certification data for example visually via an opticalinput panel of the tempering apparatus or via a data interface to anexternal device, for example to a PC, a mobile data storage or to aprinter. Correspondingly, the method preferably comprises the step:Generation of a certificate of certification data. Said certificationdata can contain a text, which is definable by the user or apredetermined text, as well as a header with the date, the time of day,the user name, serial number of the apparatus or the type of apparatus.Further, said certification data preferably comprises at least onetesting result of a testing method performed before, for example anoverall result and one or more parts of results.

It is further possible that the method is executed multiple times andsequentially and in particular by means of different components at leastin part simultaneously and repeatedly, and it is further preferred thatmultiple different of the described embodiments of the method arecombined. At a combined method, the method according to the invention isexecuted multiple times, namely in at least one of the describedembodiments. At a combined method, preferably at least one methodaccording to an embodiment for the determination of an absolute value astesting quantity is used together with at least one method according toan embodiment for the determination of a value change (said sixth orseventh embodiment of the method) as testing quantity, to determine oneor more testing quantities. Thereby, a more reliable overall testing ofthe operating condition of the tempering apparatus can be achieved.

Further features and advantages of the testing methods according to theinvention can be derived from the above description of the temperingapparatus according to the invention and its embodiments.

The method according to the invention is preferably provided for theexecution with at least one tempering apparatus according to theinvention. However, it is also possible and preferred that said methodaccording to the invention is executed with another tempering apparatus.

Further features and advantages of the invention can be derived from thesubsequent description of the figures and the figures. Same referencesigns in the figures substantially characterize the same components ormethod steps, to avoid repetitions.

FIGS. 1 to 7 are schematic drawings of different embodiments of thetempering apparatus according to the invention.

FIGS. 7 to 12 schematically show the procedure of method according tothe invention in different embodiments.

FIG. 13 schematically shows the procedure of a method, which combinesthe method according to the invention in two embodiments into a combinedmethod.

The tempering apparatus 1 is a thermocycler, which is configured for theautomatic performance of a polymerase chain reaction (PCR) in aplurality of PCR-samples. The theromocycler 1 comprises a housing 2 anda heatable cover 3. It comprises a substantially cube-like temperingblock 4, which is a component made integrally from metal. The temperingblock 4 provides at its upper side a plurality of receptacles 5, whichare configured for the reception of a plurality of sample vessels, forexample of a PCR-plate. The sample vessels and the receptacles 5 areconfigured such that a preferably large contact area is reached betweenthe exterior wall of the sample vessels and the interior wall of thereceptacles 5, a contact area which is the same for each sample vessel,to guarantee an optimal and reproducible heat transfer between thetempering block 4 and the sample vessel. The tempering 4 is heatable viathe tempering device 6, which is a Peltier element. At the temperingblock 4 further to temperature measurement devices 7, 7′ are mounted, bymeans of which the temperature of the tempering block can be measured.

The control of the tempering apparatus 1 takes place by means of thecontrol device 8. The latter in particular carries out the control ofthe tempering of the tempering block 4.

The Peltier element 6 is in a large area contact with the underside ofthe tempering block 4 such that upside of the Peltier element 6 aplurality of receptacles 5 are located.

As a functional component of the tempering control the control device 8comprises a control loop 9, to which said tempering device 6 and saidtwo temperature measurement devices 7 are assigned to. The control loop9 comprises the circuits of the controller 10, which receives as controla variable of the control loop 9 two of the actual temperature values,which are measured by the temperature measurement devices 7, 7′ via theconnections 11, 13. The testing quantity is formed for example by theformation of an average value of the both actual temperature values. Bycomparison, in particular by formation of a difference of the actualtemperature values with the adjusted temperature set values (targettemperature), the controller 10 determines a control value, whichfinally determines at which power the tempering device 6 is operated viathe connection 12.

The tempering apparatus comprises a testing device 14, by which means atesting method can be executed, by means of which at least one testingquantity is detectable, which characterizes the operating condition ofthe tempering apparatus. The testing device 14 is arranged within thetempering apparatus 1 and is structurally integrated in the controldevice 8. Via the signal line 15, the controller 10 and the signal line11 the testing device 14 is signal-connected with the temperature sensor7 and analogically with the second temperature sensor 7′. Thus, thetesting device comprises a signal-connection to the control loop 9, inparticular to the controller 10, and is in particular configured tocontrol the power, which is put out to the tempering device 6, byinfluencing the control value of the control loop. An advantage of theuse of two temperature measurement devices 7 and 7′, which are assignedto a tempering device 6, is that an additional data source can begenerated, which can give information about the operating condition ofthe apparatus in a way that not only the total break-down of a componentcan be detected but also performance deviations of the components can bedetected. The sensor 7′ not only measures the temperature which iscontrolled by means of the tempering device 6, but also at the otherhand delivers a comparison value for the data, which are measured bymeans of the sensor 7. By means of the described signal-connections ofthe testing device 14 with the components of the tempering apparatus, atesting method can be run with the tempering apparatus, withoutrequiring costly additional hardware. In this way, the reliability ofthe testing device and the tempering apparatus is improved.

A section of a storage device (data storage, not shown) is assigned tothe testing device by having stored a program code for the execution ofa testing method, in particular the testing method according to theinvention. Further, another section of a storage device is assigned tothe testing device 14, which stores the results of at least one testingmethod. The testing device 14 further comprises a starting device 18 forthe automatic starting of a testing method, wherein said starting deviceis in signal-connection with said testing device, such that an automaticstarting of said testing method is possible. The starting devicepreferably comprises a circuit logic, which is configured in theembodiment for executing the testing method after each application of atempering program, which for example can exist for performing a PCR.Also the starting device is structurally integrated in the controldevice 8.

In FIG. 2, the embodiment of the tempering apparatus according to theinvention, the thermocycler 21, comprises a testing device 24, which isrealized as an external testing device. The testing device 24 issignal-connected to the control device 28 via a signal line 17 and asignal interface 16, and signal-connected to the temperature measurementdevice 7 via the signal line 15, the controller 10 and the signal line11, and in a similar way signal-connected to the sensor 7′ and thetempering device 6. Also in this embodiment for performing a testingmethod the present structure of the tempering apparatus, in particularthe sensors, are used such that no costly additional hardware isrequired.

The testing device 24 can be integrated in an external control device,for example into an PC, by means of which a central control of thetesting methods of different tempering apparatus can take place.Preferably the testing device 24 is integrated into alaboratory-information-management-system (LIMS). The external embodimentin particular offers the advantage that testing methods, in particularmethods according to the present invention, can easily be adapted orchanged and that the testing results are more directly available for anexternal data evaluation and surveillance.

FIG. 3 shows a tempering apparatus (thermocycler) 31, which comprises acontrol loop 32, to which a first Peltier element 38 and a secondPeltier element 39 are assigned. Further, the temperature measurementdevices 7 and 7′ (temperature sensors) are assigned to the control loop32, whereby the temperature sensor 7 is assigned to the tempering device39 and the temperature sensor 7′ is assigned to the temperature device38. The temperature of the tempering block 4, which is measured by thetemperature sensor 7 thereby is such influenced substantially by thetempering device 39, which is arranged closer to said sensor 7 than thetempering device 38. Accordingly, the temperature, which is measure bythe sensor 7′ is more strongly influenced by the more closely arrangedtempering device 38. By that assignment of the temperature sensor 7 tothe Peltier element 39 and the sensor 7′ to the Peltier element 38,numerous testing methods can be performed, which improve the reliabilityof the tempering apparatus 31. On the other hand, the possibilitiesexist to generate by means of said two tempering devices 38, 39 atemperature gradient along the receptacles 5.

The testing device 14′ is signal-connected to the temperature sensor 7via the signal line 15, the controller 33 and the signal line 34 andsignal-connected to the tempering devices 39 via the signal line 15, thecontroller 33 and the signal line 35. Correspondingly, the testingdevice 14′ is signal-connected to the sensor 7′ and the tempering device38. The testing device 14′ can be configured for temporarily switchingoff the tempering device 38 or the tempering device 39, such thatcontrol takes place with only one tempering device. In this way,possibilities for further testing methods arise, which improve thereliability of the tempering apparatus by giving more detailedinformation about the operational status.

FIG. 4 shows a tempering apparatus 41, which comprises the two controlloops 42 and 42′, wherein to each control loop two tempering devices andtwo temperature measurement devices are assigned to, and wherein to eachtempering device one temperature measurement device is assigned to.Thereby, the tempering block 4 is divided into two sections 4 a and 4 b,which are separated by a material of worse heat conductibility, forexample air. Thereby, interfering influences between the control loops42 and 42′ are reduced, in particular interfering control oscillations.The control loop 42 comprises the Peltier elements 48 and 49 asactuating members, which put a temperature on the section 4 a of thetempering block, which are measured by the temperature sensor 51, whichis assigned to the tempering device 48, and the temperature measurementdevice 50, which is assigned to the tempering device 49. Said actualtemperature values are transferred to the controller 43 of the controlloop 42, whereby the control loop is closed. The control loop 42′ isconfigured analogically. The testing device 54 comprisessignal-connections to the control loops 42 and 42′ as well assignal-connections to the temperature sensors 50, 51, 50′, 51′. By saidarrangement of components in the tempering apparatus 41 it is possibleto provide further methods, in particular methods according to thepresent invention, for testing the operating condition in the temperingapparatus, whereby the reliability of the tempering apparatus 41 isimproved.

FIG. 5 shows the tempering apparatus 61, which comprises two controlloops 62 and 62′, wherein to each control loop one tempering device andone temperature measurement device is assigned to.

Further, to each tempering device exactly one temperature measurementdevice is assigned to. To the control loop 62 the Peltier element 66 isassigned to, which tempers the section 4 a of the tempering block 4, togenerate a temperature in the tempering block, which is measured by thetemperature sensor 67, which is assigned to the tempering device 66 ofthe control loop 62, and which is transferred as the temperature actualvalue to the controller 63 of the control loop 62, whereby the controlloop is closed. The control loop 62′ is configured analogically. Insteadof a tempering block divided into sections, also an integral temperingblock 4 can be used. The testing device 74 is signal-connected to thetemperature sensor 67 by means of the signal line 75, the controller 63and the signal line 64. Analogically the testing device 74 issignal-connected to the temperature sensor 67′. Further, the testingdevice 74 comprises respectively one signal-connection to the controlloops 62 and 62′ and to the tempering devices 66 and 66′. In this way,different testing methods can be performed, as described, by means ofthe components which are signal-connected to the testing device 74, forthe thermocycler 61, whereby its operational status can be reliablymonitored.

FIG. 6 shows the thermocycler 81, whose tempering block 4 consists offour sections 4 a, 4 b, 4 c and 4 d, wherein each tempering blocksection is tempered by one tempering device, and is assigned to one owncontrol loop. To the control loop 81 is assigned the Peltier element 86,which generates in the section 4 a of the tempering block 4 atemperature which is measured by the temperature sensor 87 and istransferred as temperature actual value to the controller 83 of thecontrol loop 82, whereby the control loop is closed. The control loops82′, 82″ and 82′″ are configured analogically. The testing device 94 issignal-connected to the temperature measurement device 87 via the signalline 95, the controller 83 and the signal line 84 and signal-connectedto the tempering device 86 via the signal line 95, the controller 83 andthe signal line 85. analogically, the testing device is signal-connectedto the corresponding components of the control loops 82′, 82″ and 82′″.By means of said signal-connections, numerous test methods, inparticular test methods according to the invention, can be executed withthe tempering apparatus 81, which monitor its operational status, andwhich therefore improve its reliability.

FIG. 7 shows schematically the procedure of the method 100 for thetesting of at least one first testing quantity of a tempering apparatus.Said tempering apparatus, which is appropriate for the execution of themethod and which is in particular the testing device according to theinvention and which can correspond to one of the configurationsaccording to FIGS. 1 to 6 is configured for the tempering of at leastone sample, in particular a PCR-sample. For that purpose, the temperingapparatus comprises at least one tempering block, which is configuredfor the reception of at least one sample, comprises at least one firsttempering device, which is arranged for the tempering of said at leastone tempering block, at least one first temperature measurement deviceand at least one second temperature measurement device, wherein to eachtempering device at least one temperature measurement device is assignedto, at least one control device, which is configured for the control ofthe tempering of the at least one tempering block, preferably a timer,and at least one first control loop, to which said at least one firsttempering device and said at least one first temperature measurementdevice, which is assigned to said at least one first tempering device,are assigned to.

The method 100 comprises the steps: 101 starting of the method; 102operation of at least said first tempering device for the duration of atleast one first method from at least one first time; 103 detecting atleast one measurement temperature from said at least one firsttemperature measurement device, which is assigned to said firsttempering device, at least to a second time; 104 determining at leastone first testing quantity of the tempering apparatus by using saidfirst one measurement temperature; 105 comparison of said first testingquantity with a reference quantity. At the method 100, a quantity whichis stored in the tempering apparatus and predetermined is used as thereference quantity according to step 106.

The method 110 shown in FIG. 8 shows a configuration of the method 100which additionally to the steps 101 to 105 comprises the steps: 111applying a first set temperature from at least said first time to saidcontrol loop, to which said at least one tempering device and said atleast one temperature measurement device, which is assigned to said atleast one tempering device, are assigned to; 114 use of the measurementtemperature, which is measured at said second time, as said testingquantity. Step 111 causes the control loop to temper the temperingblock, that is to heat or to cool, to reach a set temperature of thetempering block. The second time of the measurement of the temperature,which is then used as testing quantity (step 114) can be chosen suchthat the change of the temperature of the tempering block is monitoredfor example by means of said temperature measurement device. For thatpurpose, it is measured as long as within a predefined limit value nofurther changes occur any more, whereby the temperature is considered tobe adjusted at least after a further awaiting of a delay time and thetemperature measurement of the step 103 takes place. As alternative formonitoring the temperature value also a latency time (delay time) can beused, during which a stable temperature establishment is normallyexpected, in particular under consideration of the starting temperatureand the set temperature and in particular under consideration of thehistory of the temperatures at the tempering block. Said latency timecan for example be 30 seconds. If in step 105 a deviation of the testingquantity, which was determined in step 104, here a temperature from thepredefined and to be expected referenced quantity (step 106) isdetermined that the testing result is considered negatively and iscorrespondingly put out to the user.

Correspondingly, the method 110 comprises the step 107 which providesthat the testing result is put out by the testing device. Thispreferably takes place visually, for example via a display at thetempering apparatus or via an external output device which can be, forexample, the display of an external PC, which can be signal-connected tothe testing device via a data interface. The testing method 110 can beperformed in particular by a testing device of the tempering apparatusaccording to the invention. Further, the testing results areelectronically stored and documented, for example by means of adocumentation device of the tempering apparatus according to theinvention or on an external PC. The assignment of at least onetemperature measurement device to said tempering device to a networkallows to monitor the operational status of said network. The comparisonaccording to step 105 of the measured testing quantity for example ofthe temperature which pends at the sensor at a certain time, with apredetermined comparison quantity, which is expected to occur undernormal operating condition of the tempering apparatus, gives informationabout if an operational malfunction at said network is present or not.This way, the break-down of said component network can be detected. Inparticular, if the starting of the method takes place automatically, forexample after each tenth execution of a tempering program, thereliability of the tempering apparatus can be improved.

FIG. 9 shows the method 120, which additionally to testing of a firsttesting quantity according to the steps 101 to 105 refers to the testingof a second testing quantity of said tempering apparatus. The method isfor example appropriate for a tempering apparatus, to whose firstcontrol loop at least one second tempering device and at least onesecond temperature measurement device, which is assigned to said atleast one second tempering device, are assigned to. Further the methodis appropriate for a tempering apparatus, which comprises at least onesecond control loop, which is different from said first control loop,wherein to said second control loop at least one second tempering deviceand at least one second temperature measurement device, which isassigned to said at least one second tempering device, are assigned to.Examples for such tempering apparatus are the thermocyclers shown in theFIGS. 3 to 6.

The method 120 comprises the steps: 101 starting of the method; 102operation of at least said first tempering device for the duration of atleast one first period from at least one first time; 103 detecting atleast one measurement temperature from said at least one firsttemperature measurement device, which is assigned to said firsttempering device, at least at a second time; 104 detecting at least onefirst testing quantity of the tempering apparatus by using said at leastone measurement temperature; 105 comparison of said first testingquantity with a reference quantity, which is said second testingquantity (step 106 b). Further, the method 120 provides thatsimultaneously or not simultaneously additionally to the steps 102 to105 the steps are performed: 102′ operation of said second temperingdevice for the duration of at least a first period from at least a firsttime; 103′ detecting at least one measurement temperature from said atleast one second temperature measurement device, which is assigned tosaid second tempering device, at least at a second time; 104′determining at least one second testing quantity of the temperingapparatus by using said at least one measurement temperature; 105′comparison of said second testing quantity with a reference quantity,which is said first testing quantity (step 106 b). Alternatively oradditionally, each testing quantity can be compared with a storedreference quantity. An advantage at the determination of the secondtesting quantity and therefore an advantage of the method 120 is thatthe tempering and temperature measurement devices can monitor eachother, such that a better monitoring of the operational status of thetempering apparatus is possible, which therefore becomes more reliable.

FIG. 10 shows the method 130, which additionally to the method steps 101to 105 comprises the steps: 131 detecting at least one measurementtemperature from said at least one temperature measurement device, whichis assigned to said tempering device, at a third time; 134 forming thedifference of two measurement temperatures, from which the one wasmeasured at said second time and the other was measured at said thirdtime, forming of a second period, which corresponds to the difference ofsaid third time and said second time, and using said second period assaid first testing quantity. The testing quantity “period” is determinedin relation to a predefined (constant) temperature difference as changeof values. Also the reference quantity, which is used for the comparisonwith said testing quantity, was determined and defined in relation tosaid constant temperature difference. Therefore a quotient exists, evenif it is not explicitly calculated in said embodiment of the method.This has a dimension of a temporal change of values, in particular of arate and in particular of a temperature change velocity. By means ofsuch a (temporal) change of values not only the break-down of a networkof tempering device and at least one assigned temperature measurementdevice can be determined but also according to method 140 the capabilityof said network can be tested. A temperature difference, time differenceor the quotient of both values is determined by having either a timedifference predefined and determining the resulting temperaturedifference, or alternatively by determining, in which time apredetermined temperature difference is formed.

The second of said alternatives is realized in the method 140 shown inthe FIG. 11, which additionally to the method steps 101 to 105 and 131and 134 comprises the steps: 141 repeated detection of at least onechanging measurement temperature from said at least first temperaturemeasurement device, which is assigned to said first tempering device, attimes after said second time, comparison of said changing measurementtemperature with a comparison temperature; 143 detection of a time, atwhich said changing measurement temperature has reached said comparisontemperature within the limits of a tolerance, and using said time assaid third time. The time difference, determined in step 104 as testingquantity, can either be compared with a stored quantity (step 106) orwith another testing quantity (step 106 b).

In FIG. 12 the method 150 is shown, at which two time differences aredetermined as testing quantities. It can, for example, be executed by atempering apparatus, at which to one tempering device two temperaturemeasurement devices are assigned to. Examples for such a temperingapparatus are the thermocyclers shown in FIGS. 1 and 2. The temperingdevice with its assigned first temperature measurement device forms afirst component network and forms with its assigned second temperaturemeasurement device a second component network, wherein for each networkan own testing quantity for the characterization of the capability ofthe network is detected. The method 150 starts automatically (step 101)after the execution of a tempering program and tempers the temperingblock with the tempering device from a first time (102). For the controlloop of the tempering apparatus, to which the tempering device isassigned to, for example a set value is predefined. By means of the twotemperature measurement devices, which are assigned to said temperingdevice, respectively two temperature values are determined at two times.The both times of the temperature measurements, namely firstly saidsecond time and thereafter said third time are determined, before theset temperature is reached. The predefined constant temperaturedifference, upon whose expiration said third time is determined,amounts, for example, 30° C. The time difference between the third andsecond time, which is assigned to the first component network and whichis determined as the first testing quantity, is, for example. 30seconds, the second testing quantity, which is assigned to the secondcomponent network, is, for example, 35 seconds. Assumed, that the(reference-)value which is under the chosen conditions normallyexpected, for the time difference would be 30 seconds with a toleranceof 0.5 seconds. Then either both temperature sensors are defect or thetempering device is defect. It is less probable that two components atthe same time show a malfunction than that only one component ismalfunctioning. Therefore, in that case it is more probable that thetempering device provides a malfunction, for example a malfunctioningconnection to the tempering block. In this way, by the configuration ofthe tempering apparatus using two sensors per control loop and temperingdevice as well as the method according to the invention, additionalsafety at the analysis of the operational status of the temperingapparatus can be gained.

FIG. 13 shows a method 160, at which two differently configured methodsaccording to the invention are combined to one testing method, whereby aespecially reliable testing of the operating condition of a temperingapparatus is achieved. The method 160 is for example executed by atempering apparatus, at which to one tempering device two temperaturemeasurement devices are assigned to, see FIGS. 1 and 2. One firsttesting quantity and one second testing quantity are determined in atemporally overlapping procedure. The method is started by a manual userinput, which for example takes place via an input panel of the temperingapparatus, step 101. At the control loop of the tempering device a setvalue is applied (162) and the tempering device is caused to heat. Thefirst testing quantity is a difference of two temperature values, whichare detected by the temperature sensors, which are assigned to thetempering device, namely at said second time (103, 163) and whosedifference is used as the first testing quantity (164, 104). To makesure that the temperature in the tempering block is finally adjusted atthe positions of both temperature sensors, said second time ispreferably chosen such that a delay time of for example 30 seconds afterreaching of the temperature of the set value is included, during whichthe temperature stabilizes.

The second testing quantity in the method 160 is the period which isrequired for reaching of a predefined temperature difference. Itcorresponds thus to a temperature change velocity, without that howeverthe quotient of temperature- and time difference is explicitlycalculated. The period is determined by measuring not only at the timesof said second time (103) of the method 160, but also additionally usingtwo further times and two further temperature values. That times are athird time (131) and a further second time (103′) wherein said thirdtime is provided during the tempering, thus after said first time andafter said further said second time. Said further second time (103′) ispreferably chosen such that the temperature set value has not yetreached such set temperature between the times provides and, forexample, increasing profile, in particular a substantially ramp-shapedprofile. The measured temperature difference can be delivered as wellfrom said first or said second temperature sensor, or a combination ofthe sensors is used, for example by forming an average value.

The first testing quantity as well as the second testing quantity arecompared with stored reference values (105, 106; 105″, 106″), andrespectively a partly result of the testing method is put out (107,107″). With said combined, temporally overlapping method, further testdata can be determined in a time saving manner, which give informationabout the operational status of the tempering apparatus. Preferably,such a combined testing method comprises further configurations of themethod according to the invention, by for example after thedetermination of the first testing quantity, which was determined duringthe step of heating, determining further testing quantities, which aredetermined during cooling steps. For example, in said combined methodsequentially the temperature values 35° C. (starting value), 95° C., 35°C., 95° C., 75° C., 55° C., 35° C. and 4° C. can be approached, and ateach reaching of said set values a testing quantity can be determined.Thus, a testing method is created, which gives information on theoperational capability of the tempering apparatus in different,operationally intended temperature regions and also on the heatingperformance as well as the cooling performance. Such a combined testmethod gives a especially complete information on the operatingcondition of the tempering apparatus.

The invention claimed is:
 1. Tempering apparatus (1; 21; 31; 41; 61; 81) for the execution of a tempering program for at least one sample, comprising: at least one tempering block (4) configured for the reception of at least one sample, at least one tempering device (6; 38; 39; 48; 49; 86) arranged for the tempering of said at least one tempering block (4), at least one temperature measurement device assigned to said at least one tempering device, at least one control loop (9; 32; 42; 62; 82) for the regulation of a temperature, to which said at least one tempering device and said at least one temperature measurement device, which is assigned to said at least one tempering device, are assigned to, at least one control device (8; 58; 68; 88) configured for the control of the tempering of the at least one tempering block, characterized in that the tempering apparatus comprises at least two temperature measurement devices (7; 50; 51; 67; 87) assigned to at least one control loop, wherein said at least two temperature measurement devices serve as the measuring elements of the at least one control loop and comprise at least a first and a second temperature measurement device, and that to the tempering apparatus a at least one testing device (14; 24; 14′; 54; 74; 94) for the execution of a testing method is assigned to, wherein said testing device comprises a signal-connection (15; 17; 75; 95) to said at least first and second temperature measurement devices (7; 50; 51; 67; 87), such that by means of said signal-connection (15; 17; 75; 95) at least one testing quantity and a second testing quantity of the tempering apparatus are detectable, which characterizes the operational status of the tempering apparatus, wherein the tempering apparatus is configured for the execution of the testing method, which comprises the steps: starting the method (101); operation of at least said first tempering device for the duration of at least one first period from at least one first time (102); detecting at least one measurement temperature from said at least one first temperature measurement device, which serves as a measuring element of the at least one control loop and which is assigned to said first tempering device, at least at a second time (103); determining at least one first testing quantity of the tempering apparatus by using said at least one measurement temperature (104); comparison of said first testing quantity with a reference quantity (105), wherein said reference quantity is said second testing quantity.
 2. Tempering apparatus according to claim 1, characterized in that it comprises at least one control loop, to which at least two tempering devices and at least two temperature measurement devices are assigned to, wherein to each tempering device at least one temperature measurement device is assigned to.
 3. Tempering apparatus according to claim 1, characterized in that it further comprises a starting device (18) for the starting of a testing method, wherein said starting device is in signal-connection with said testing device.
 4. Tempering apparatus according to claim 3, characterized in that said starting device is configured for the manual starting of a testing method.
 5. Tempering apparatus according to any one of claims 1-4, characterized in that it provides the function of a thermocycler, which is appropriate for the performance of a PCR-reaction in at least one PCR-sample. 